Glucose-sensitive insulin with attenuation of hypoglycaemia

• Published in: Nature (London) Vol. 634; no. 8035; pp. 944 - 951
• Main Authors: Hoeg-Jensen, Thomas, Kruse, Thomas, Brand, Christian L., Sturis, Jeppe, Fledelius, Christian, Nielsen, Peter K., Nishimura, Erica, Madsen, Alice R., Lykke, Lennart, Halskov, Kim S., Koščová, Simona, Kotek, Vladislav, Davis, Anthony P., Tromans, Robert A., Tomsett, Michael, Peñuelas-Haro, Guillem, Leonard, Daniel J., Orchard, Michael G., Chapman, Andy, Invernizzi, Gaetano, Johansson, Eva, Granata, Daniele, Hansen, Bo F., Pedersen, Thomas A., Kildegaard, Jonas, Pedersen, Karen-Margrethe, Refsgaard, Hanne H. F., Alifrangis, Lene, Fels, Johannes J., Neutzsky-Wulff, Anita V., Sauerberg, Per, Slaaby, Rita
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-10-2024; Nature Publishing Group
• Subjects: 101/58; 13/95; 140/131; 631/92/469; 64/86; 692/163/2743/137/138; 96/1; Biological activity; Blood; Blood glucose; Blood levels; Design; Diabetes; Diabetes mellitus; Glucose; Humanities and Social Sciences; Hypoglycemia; Insulin; multidisciplinary; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-08042-3

The risk of inducing hypoglycaemia (low blood glucose) constitutes the main challenge associated with insulin therapy for diabetes
1
,
2
. Insulin doses must be adjusted to ensure that blood glucose values are within the normal range, but matching insulin doses to fluctuating glucose levels is difficult because even a slightly higher insulin dose than needed can lead to a hypoglycaemic incidence, which can be anything from uncomfortable to life-threatening. It has therefore been a long-standing goal to engineer a glucose-sensitive insulin that can auto-adjust its bioactivity in a reversible manner according to ambient glucose levels to ultimately achieve better glycaemic control while lowering the risk of hypoglycaemia
3
. Here we report the design and properties of NNC2215, an insulin conjugate with bioactivity that is reversibly responsive to a glucose range relevant for diabetes, as demonstrated in vitro and in vivo. NNC2215 was engineered by conjugating a glucose-binding macrocycle
4
and a glucoside to insulin, thereby introducing a switch that can open and close in response to glucose and thereby equilibrate insulin between active and less-active conformations. The insulin receptor affinity for NNC2215 increased 3.2-fold when the glucose concentration was increased from 3 to 20 mM. In animal studies, the glucose-sensitive bioactivity of NNC2215 was demonstrated to lead to protection against hypoglycaemia while partially covering glucose excursions.
NNC2215 is an insulin conjugate that can reversibly adjust its bioactivity in response to a diabetes-relevant glucose range in vivo.